Cataract is the leading cause of vision loss (accounting for ~45% of blindness worldwide) and represents the most common reason for eye surgery. A long-term goal of our research is to map, identify and characterize common and novel genetic determinants of cataract. In Specific Aim 1 of this proposal, genetic linkage analysis with microsatellite markers and DNA amplification/sequencing techniques will be used to map and identify genetic mutations underlying autosomal dominant cataract in four or more pedigrees from the St. Louis population. In Specific Aim 2, DNA amplification and sequencing techniques will be used to characterize the nature, pattern and frequency of nucleotide variation in genes linked with autosomal dominant cataract. In Specific Aim 3, linkage disequilibrium analysis and DNA amplification/sequencing techniques will be used to test for association between genes for hereditary cataract and age-related cataract. In Specific Aim 4, DNA expression methods, analytical biochemical techniques and molecular cell biology techniques will be used to characterize the functional consequences of mutations in the genes for alphaA-crystallin and betaB1-crystallin that are associated with autosomal dominant cataract linked to chromosomes 21q and 22q, respectively. Results from these studies will lead to 1. A molecular basis for understanding the pathogenetic mechanisms of cataract development, 2. The design of DNA-based diagnostics and therapeutics for cataract that are targeted to the underlying defects and 3. Better evaluation of environmental risk factors for cataract, thereby enabling genetically susceptible individuals to choose a lifestyle that delays or even prevents cataract onset.